Cancer genomics is revealing comprehensively somatic mutations that may constitute the root cause of disease. These findings suggest novel mechanisms for cancer initiation and progression, and new ways we might treat cancer in the future. Recently, a genome-wide sequencing study identified mutations in the metabolic enzyme IDH1 in samples from patients with glioblastoma multiforms, which are among the most lethal cancers with survival of only months after their diagnosis. (Parsons D. W. et al., Science 321, 1807-1812, 2008). Subsequent analyses revealed that mutations in IDH1 are common (70%-80%) in grade II, III gliomas and secondary glioblastomas and that patients lacking IDH1 mutations often harbor mutations in IDH2, which shares 70% identity with IDH1. (Yan H. et al., N Engl J Med 360, 765-773, 2009; Bleeker F. E. et al., Hum Mutat 30, 7-11, 2009; Balss J. et al., Acta Neuropathol 116, 597-602, 2008). More recently, IDH1/2 mutations have been observed in acute myeloid leukemia (AML) and rare cases have been reported in other cancers. (Ward P. S. et al., Cancer Cell 17, 225-234, 2010; Exp. Med. 207, 339-344, 2010; Mardis E. R. et al., N Engl J Med 361, 1058-1066, 2009). Notably, all mutations in IDH1/2 are heterozygous and the majority of them affect a particular codon (R132 in IDH1 and the analogous codon, R172, in IDH2) suggesting the gene may contribute to carcinogenesis as an oncogene rather than a tumor suppressor through a gain of function.
IDH1/2 are NADP+-dependent isocitrate dehydrogenases that normally mediate oxidative decarboxylation of isocitrate to α-ketoglutarate (α-KG) via the conversion of NADP+ to NADPH. Mutations in IDH1/2 appear to have two functional consequences for the enzymes' activities: i) a decreased ability to convert isocitrate to α-KG; and ii) a new ability to reduce α-KG to (R)-2-hydroxyglutarate (2-HG) using NADPH (Ward et al., supra; Dang, L. et al., Nature 462, 739-744, 2009). Indeed 2-HG levels are elevated >50-fold in samples from patients with IDH1/2-mutations. This observation has motivated study of 2-HG as a disease biomarker, as well as deeper study into the molecular mechanism by which this putative ‘oncometabolite’ might contribute to disease. Indeed, 2-HG could interfere with a wide range of processes, such as those regulated by α-KG-dependent, iron-dependent dioxygenases; these processes include the response to hypoxic stress (mediated by EglN prolyl hydroxylases), DNA modification (mediated by TET2, a 5-methylcytosine hydroxylase), and histone methylation (mediated by JmjC-containing demethylases), among others (Figueroa M. E. et al., Cancer Cell, 18, 553-567, 2010; Christensen, B. C. et al., J. Natl. Cancer Inst. 103, 2, 143-53, 2011; Zhao, S. et al., Science, 324, 261-265, 2009; Xu, W. et al., Cancer Cell, 19, 17-30, 2011). Thus, the development of small molecules that inhibit the 2-HG-generating activity of IDH1/2 mutants in cells is important in cancer cell biology and drug development.
Point mutations IDH1 and IDH2 occur early in the pathogenesis of gliomas. Reitman reports that the study of 200 metabolites in human oligodendroglioma (HOG) cells to determine the effects of expression of IDH1 and IDH2 mutants showed that the levels of amino acids, glutathione metabolites, choline derivatives, and tricarboxylic acid (TCA) cycle intermediates were altered in mutant IDH1- and IDH2-expressing cells. (Reitman Z. J. et al., Proc. Natl. Acad. Sci. 2011, 108(8) 3270-3275). Furthermore, N-acetyl-aspartyl-glutamate (NAAG), a common dipeptide in brain, was 50-fold reduced in cells expressing IDH1 mutants and 8.3-fold reduced in cells expressing IDH2 mutants.
Hartmann et al., (US 20100291590) discloses a method for the diagnosis of a brain tumor using the presence/absence of a particular IDH1 mutation as a marker. Vogelstein et al. (WO 2010/028099) discloses that mutations in IDH1 and IDH2 are related to astrocytomas, oligodendrogliomas and glioblastomas. Dang et al., (WO 2010/105243) discloses methods for the treatment of isocitrate dehydrogenase related proliferative disorders.
Glioblastoma is the most frequent and most malignant human brain tumor. The prognosis remains very poor, with most patients dying within 1 year after diagnosis. (Ohgaki et al. American Journal of Pathology, 170(5), 2007, 1445-1453). There exists a need to develop effective treatments against proliferative disorders including glioblastoma and acute myeloid leukemia. Thus, there exists a need to focus on developing compounds that inhibit mutated IDH1/2 with selectivity over wild-type IDH1/2 with the goal of targeting cancer cells selectively over normal cell. That said, there is also a need for advancing compounds that target both mutant and wild-type IDH1/2 since cancer cells which harbor mutant IDH alleles are dependent on the wild-type allele for proliferation, suggesting inhibition of wild-type IDH may also prove valuable for treating cancer (Ward P. S. et al., Cancer Cell 17, 225-234, 2010).